Originally regarded as a simple barrier against passive leakage of fluid into lung airspaces critical for gas exchange, the alveolar epithelium is now viewed as a key regulator of alveolar homeostasis. Furthermore, alterations in alveolar epithelium are central to the pathogenesis of a number of diseases impacting respiratory health including idiopathic pulmonary fibrosis (IPF) and emphysema, making it important to understand mechanisms responsible for its normal maintenance and repair following injury. My research program is thematically focused on alveolar epithelial cell (AEC) plasticity/?reprogramming?, with the overall goal of characterizing the molecular basis of AEC function and phenotype in order to elucidate mechanisms leading to aberrant repair and develop strategies for improving outcome following injury, consistent with the mission of NHLBI. Our work to date has contributed to new paradigms in AEC biology, including demonstration of an active role for alveolar epithelial type I (AT1) cells in alveolar homeostasis, AEC plasticity, a central role for alveolar epithelium in pulmonary fibrosis, discovery of a novel role of tight junctions (TJ) in regulation of lung stem/progenitor cell homeostasis, and elucidation of key pathways regulating AEC differentiation. Building on this work, we will focus going forward on complementary areas of 1) regulation of normal AEC phenotype/differentiation, 2) role of AEC in lung fibrosis and 3) regulation of endogenous lung stem/progenitor cell homeostasis coordinated by interactions with TJ, in order to address key gaps in our understanding of normal AEC progenitor potential/differentiation and disruption in disease. Success will be ensured by a) synergistic interactions among a strong team with expertise in AEC differentiation, lung development, epigenetics/bioinformatics and regenerative medicine and b) use of innovative models (e.g., induced pluripotent cells (iPSC) from normal and IPF patients) to investigate AEC differentiation in health and disease. Application of genome-wide genomic and high-throughput technologies will provide potentially transformative insights into previously unexplored cell-specific epigenetic (especially histone) modifications regulating normal and aberrant differentiation of normal and IPF AEC. Novel insights regarding regulation of lung stem/progenitor function by intracellular transduction of signals from TJ have the potential to be harnessed to augment lung regeneration after injury. Deliverables with broad application to the lung research community include improved methods for AT1 cell isolation, novel AT1 cell markers/Cre lines, and genome-wide datasets to be deposited as a shared resource. Our integrated team approach using primary (including human) AEC, spheroid cultures and iPSC, together with genome-wide transcriptomic/epigenomic analyses and disease modelling, to address critical questions related to AEC maintenance and repair has significant translational potential. Although aspects of the program are potentially high-risk, these are precisely the types of studies that provide new innovative research opportunities and will benefit most from the long-term support provided by this award.